The present invention relates to a medicine useful for the prevention and treatment of cartilaginous diseases. More particularly, the present invention relates to a therapeutic agent for cartilaginous diseases, an accelerator for chondrocyte proliferation and an accelerator for proteoglycan production comprising HGF (Hepatocyte Growth Factor) as an active component.
Cartilage is a connective tissue composed of chondrocytes and matrices surrounding them, and exists in articulatio, intervertebral disk of spina, costal cartilage, auricle, external acoustic meatus, pubic symphysis, throat tectum and the like. Cartilage is composed of chondrocytes and cartilage matrices produced by the chondrocytes, and the cartilage matrix consists mainly of a fiber component such as a collagen fiber, proteoglycan and water. Cartilage can be classified into hyaline cartilage (costal cartilage, throat cartilage, articular cartilage and the like), elastic cartilage (auricle cartilage and the like) and fibrocartilage (intervertebral disk cartilage, pubic bone cartilage, articular cartilage and the like) depending on the mixing condition of a cartilage matrix. In the aforesaid cartilage matrix, it is said that the collagen fiber concerns the stiffness and strength of cartilage against tension and shear force, proteoglycan concerns the strength of cartilage against compression force, and water manifests a feature as a viscoelastic material for an organism tissue, and for example, in the articular cartilage, 78.6% of the weight of cartilage is occupied by water, 20% is occupied by collagen and 7% is occupied by proteoglycan. The effect of cartilage includes the reduction in abrasion of epiphysis (cartilage between bones), maintenance of elasticity (auricle cartilage and the like), and motion function (rib cartilage, pubic bone cartilage and the like).
As described above, cartilage has an important effect for maintaining the function of an organism, and conventionally, there are known various disorders caused by cartilage diseases, including, for example, chondrodystrophy, osteoarthritis, diastrophic discopathy, failure in restoration and cure of fracture and the like. Particularly, there has been a remarkable increase in the number of the patient suffering from anthropathy because of the arrival an aging society, the increase of injury due to sports and the appearance of occupational diseases represented by keypuncher disease and the like, and there is desired the development of medical care in this field.
Various therapeutic methods have been conventionally tried for the treatment of cartilage diseases. They were not intended for direct solution of causes, but were only nosotropic methods, for example, a method in which disorder such as pain due to the disease is inhibited by administering an antiphlogistic; a method in which the motion of an articulatio is made smooth by injecting a hyaluronic acid preparation into the articulatio, and the like.
As described above, radical therapeutics for articular disorders has not been found, and there are many patients suffering from osteoarthritis, therefore, an effective therapeutic method for articular disorders is eagerly desired.
The present inventors have been studied intensely to solve the above-mentioned problems. As a result, it has been found that HGF promotes the proliferation of a chondrocyte, has an effect to promote the production of proteoglycan, and is effective for the treatment of various disorders caused by cartilaginous diseases, and the present invention has been completed.
The above-described HGF is a protein which was found as a factor to proliferate liver parenchyma cells in vitro (Biochem Biophys Res Commun, 122, 1450, 1984; Proc. Natl. Acad. Sci. USA, 83, 6489, 1986; FEBS Letter, 224, 311, 1987; Nature, 342, 440, 1989; Proc. Natl. Acad. Sci. USA, 87, 3200, 1990). It has become apparent as a result of the recent studies by many researchers including the present inventors that HGF, which was found as a factor to specifically proliferate liver parenchyma cells, manifests various activities such as the cure of tissue injury in vivo, and HGF is expected to be not only a research object but also therapeutic agents applied to human and animals.
It is known that HGF is produced mainly by mesenchymal cells, and it has become clear that so-called paracrine mechanism exists in which HGF is optionally supplied from adjacent cells. However, it is believed that HGF is supplied also by so-called endocrine mechanism since when liver or kidney is injured, the production of HGF is increased also in the organs which are not injured, for example lung and the like.
Regarding the receptor of HGF, it has been identified form the recent studies that c-Met proto-oncogene codes the HGF receptor (Bottaro et al., Science 251, 802-804, 1991; Naldini et al., Oncogene 6, 501-504, 1991).
As described above, though various information are known regarding HGF, the chondrocyte growth accelerating effect and proteoglycan production accelerating effect are novel knowledge which are conventionally not known, and the present invention accomplished based on the knowledge provides a medicine useful for the treatment of various disorders caused by cartilaginous diseases.
The present invention is a therapeutic agent for cartilaginous diseases comprising HGF as an active component.
Further, the present invention relates to an accelerator for chondrocyte proliferation comprising HGF as an active component; an accelerator for proteoglycan production comprising HGF as an active component; and a therapeutic method for cartilaginous diseases of human or mammals comprising administering an effective amount of HGF.
The above-described HGF may be one derived from the tissue or blood component of human or animals, or one produced by gene recombination.
The active component HGF is effective for the treatment and prevention of various disorders caused by cartilaginous diseases, since HGF promotes the growth of chondrocytes and promotes the production of proteoglycan.